problem solving in cancer and fertility
TRANSCRIPT
Problem Solving in Cancer and Fertility
Problem Solvingin Cancer and FertilityEdited by
Eleni M Karapanagiotou, MD, PhDConsultant Medical Oncologist, Guy’s Cancer Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Julia Kopeika, MD, MRCOG, PhDConsultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery, Assisted Conception Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Ruth E Board, BSc, MBChB, PhD, FRCPConsultant in Medical Oncology, Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK
Caroline Archer, BSc, MBBS, FRCPConsultant Medical Oncologist, Portsmouth Oncology Centre, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
Melanie C Davies, MBBS, MA, MRCP, FRCOGConsultant Gynaecologist, Reproductive Medicine Unit, University College London Hospitals, London, UK
Janine Mansi, MD, FRCP, FACP(UK)Consultant Medical Oncologist, Guy’s and St Thomas’ NHS Foundation Trust and Biomedical Research Centre, King’s College London, UK
Published in association with the Association of Cancer Physicians
E B N H E A L T H
O X F O R D , U K
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Contents
Contributors viiiPreface xiiiAcknowledgements xv
SECTION ONE Perspectives
01 The Effects of Cancer and its Treatment on Female Fertility, Richard A. Anderson
1
02 Fertility Preservation in Women, Julia Kopeika 7
03 Fertility Preservation in Men, Maj Shabbir 12
04 Management of Cancer in Pregnancy, Kate Harding 19
05 Drugs Used to Treat Cancer During Pregnancy, Alison L. Jones, Ruth E. Board
24
06 Pregnancy After Diagnosis and Treatment of Cancer, Danielle Crawley, Eleni M. Karapanagiotou
30
07 Fertility Outcome in Men After Cancer Treatment, Allan Pacey 34
08 Premature Ovarian Insufficiency—Diagnosis and Overview of Survivorship Issues, Melanie C. Davies
38
09 Egg Donation and Surrogacy, Mari Isdale, Raj Mathur 43
10 Hormone Replacement Options for Women with Premature Ovarian Insufficiency After Cancer Treatments, Lisa Webber
50
11 Hereditary Cancer Syndromes and Fertility, Annabelle Kerr, Charlotte Tomlinson, Vishakha Tripathi
55
12 Counselling—Cancer and Fertility: What Does a Counsellor in a Fertility Clinic Do?, Carmel Dennehy
60
13 Ethical Issues in Fertility Preservation for Cancer Patients, Francoise Shenfield
65
SECTION TWO Case Studies
01 Fertility Preservation in Early Breast Cancer, Chara Stavraka, Julia Kopeika 69
02 Fertility Preservation in Cervical Cancer, Jonathan Riley, Nicholas Wood 73
vi Contents
03 Fertility Preservation in Testicular Cancer, Majed Shabbir, Neerujah Balachandren
78
04 Post-Partum Fertility Preservation, Lukasz Polanski, Julia Kopeika 82
05 Colon Cancer With Inherited Genetics: Lynch Syndrome, Christopher Williams, Jenny Seligmann
87
06 Ovarian Tissue Cryopreservation in the Setting of Recurrent Cancer and Escalation of Treatment, Dalia Khalife, Julia Kopeika
92
07 Fertility Preservation in a Young Man Unable to Produce a Sperm Sample, Saira Khalique, Philippa Sangster
99
08 A Case of an Unexpected Conception in a Patient With Metastatic Melanoma on Immune Checkpoint Inhibitors, Prerana Huddar, Ruth Board
105
09 An Unexpected Pregnancy in a Woman With Metastatic Breast Cancer, Rachel Broadbent, Alia Alchawaf, Laura Horsley
111
10 Accidental Pregnancy During Chemotherapy Treatment, Sarah Hunter, Catherine Oakley, Eleni Karapanagiotou
115
11 A Case of Lung Cancer Diagnosed During Pregnancy, Alexandra R. Lewis, Catherine Nelson-Piercy
119
12 A Woman Who Wishes to Become Pregnant Following Treatment for ER+ Breast Cancer, Joanna Hack, Eleni M. Karapanagiotou
123
13 Pregnancy After Bone Marrow Transplant, Helen Hockings, Melanie C. Davies
126
14 Woman With Premature Ovarian Insufficiency After Stem Cell Transplant and Total Body Irradiation Seeking Fertility Treatment, Guy Morris, Melanie C. Davies
132
15 Premature Ovarian Insufficiency, HRT and VTE, Meera Chauhan, Sean Dulloo, Oyeyemi Akala, Mari Thomas
137
16 Premature Ovarian Insufficiency and HRT in Breast Cancer: Management of Vaginal Symptoms and Hot Flushes, Kathryn Herring, Daniel Rea
141
17 Premature Ovarian Insufficiency and Bone Health, Emily Goode, Janine Mansi
146
18 Pregnancy After Testicular Failure Caused by Cancer Treatment, Sofia Nyberg, Maj Shabbir, Julia Kopeika
152
19 Risk Reducing Bilateral Salpingo-Oophorectomy in BRCA Positive Breast Cancer, Kathryn Baxter, Nick Wood, Sarah Moon
157
20 A Case of a Pregnancy Following Radical Trachelectomy, Yusuf Beebeejaun, Julia Kopeika
162
viiContents
21 A Case of Ovarian Tissue Cryopreservation in the Setting of Non-Hodgkin’s Lymphoma, Dalia Khalife, Julia Kopeika
167
22 A Case of Breast Cancer in a Transgender Man With BRCA2 Mutation, Alison Berner, Leighton Seal, Katie Snape
172
23 A Case of Testicular Cancer in a Gay Man, Alison Berner, Daniel Hughes, Daniel Saunders
177
Index 181
Contributors
Dr Oyeyemi Akala, Medical Oncology Specialist Registrar, University Hospitals of Leicester NHS Trust, Leicester
[email protected] Alia Alchawaf, Specialist Registrar in Medical Oncology, The Christie NHS
Foundation Trust, Manchester [email protected] Richard A Anderson, Elsie Inglis Professor of Clinical Reproductive Science,
MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh [email protected] Neerujah Balachandren, Clinical Research Fellow in Reproductive Medicine,
University College London Hospital, London [email protected] Kathryn Baxter, Obstetric and Gynaecology Specialist Trainee, Lancashire Teaching
Hospitals NHS Foundation Trust, Preston [email protected] Yusuf Beebeejaun, Clinical Research Fellow, King’s Fertility, King’s College Hospital,
London [email protected] Dr Alison Berner, Speciality Trainee and Clinical Research Fellow in Medical
Oncology, Barts Cancer Institute and Specialist Registrar in Gender Identity, Tavistock and Portman NHS Foundation Trust, London
[email protected] Dr Ruth E Board, Consultant in Medical Oncology, Rosemere Cancer Centre, Royal
Preston Hospital, Preston [email protected] Dr Rachel Broadbent, Specialist Registrar in Medical Oncology, The Christie NHS
Foundation Trust, Manchester [email protected] Meera Chauhan, Medical Oncology Specialist Registrar, University Hospitals of
Leicester NHS Trust [email protected] Danielle Crawley, Specialist Registrar Medical Oncology, Guy’s and St Thomas NHS
Foundation Trust, London [email protected] Melanie C Davies, Consultant Gynaecologist, Reproductive Medicine Unit,
University College London Hospitals, London [email protected]
ixContributors
Carmel Dennehy, Specialist Counsellor and Psychotherapist in Reproductive Medicine, University College London Hospital, London
[email protected] Dr Sean Dulloo, Medical Oncology Specialist Registrar, University Hospitals of
Leicester NHS Trust, Leicester [email protected] Emily Goode, Specialist Registrar Medical Oncology, The Royal Marsden Hospital,
London [email protected] Joanna Hack, Department of Medical Oncology, University Hospital Southampton
NHS Foundation Trust, Southampton [email protected] Dr Kate Harding, Consultant Obstetrician, Guy’s and St Thomas’ Foundation Trust,
London [email protected] Dr Kathryn Herring, SpR Medical Oncology, Queen Elizabeth Hospital, Edgbaston,
Birmingham [email protected] Helen Hockings, Medical Oncology Specialist Registrar, St Bartholomew’s Hospital,
London [email protected] Laura Horsley, Consultant Medical Oncologist, The Christie NHS Foundation
Trust, Manchester. [email protected] Prerana Huddar, ST3 Medical Oncology, Rosemere Cancer Centre, Royal Preston
Hospital, Lancashire Teaching Hospitals NHS Trust, Preston [email protected] Dr Daniel Johnathan Hughes, Specialist Registrar in Medical Oncology, UCL Cancer
Institute, University College, London [email protected] Sarah Hunter, Medical Oncology Registrar, Guy’s and St Thomas’ Hospital, London [email protected] Mari Isdale, Senior Clinical Fellow IVF and Reproductive Medicine, Manchester
Foundation Trust, Manchester [email protected] Alison Jones, Consultant Medical Oncologist, The Royal Free London NHS
Foundation Trust, London [email protected] Dr Eleni M Karapanagiotou, Consultant Medical Oncologist, Guy’s Cancer Centre,
Guy’s and St Thomas’ NHS Foundation Trust, London [email protected]
x Contributors
Annabelle Kerr, Genetic Counsellor, Clinical Genetics Service, Guy’s and St Thomas’ NHS Foundation Trust, London
[email protected] Dalia Khalife, Specialist in Obstetrics and Gynecology, Subspecialist in
Reproductive Endocrinology and Infertility, Jumeirah American Clinic, Dubai, United Arab Emirates
[email protected] Saira Khalique, Speciality Registrar in Medical Oncology, University College
London Hospitals NHS Foundation Trust, London [email protected] Julia Kopeika, Consultant Gynaecologist and Subspecialist in Reproductive
Medicine and Surgery, Assisted Conception Unit, Guy’s & St Thomas’ NHS Foundation Trust, London
[email protected] Dr Alexandra R Lewis, Clinical Fellow, Department of Medical Oncology, The Christie
Hospital NHS Foundation Trust, Manchester [email protected] Janine Mansi, Consultant Medical Oncologist, Guy’s and St Thomas’ NHS
Foundation Trust and Biomedical Research Centre, King’s College London [email protected] Raj Mathur, Consultant in Reproductive Medicine and Surgery, Manchester
University NHS Foundation Trust. [email protected] Dr Sarah Moon, Consultant Oncologist, University Hospitals of Morecambe Bay [email protected] Dr Guy Morris, Clinical Fellow in Reproductive Medicine, Reproductive Medicine
Unit, Elizabeth Garrett Anderson Hospital, University College London Hospitals, London
[email protected] Professor Cathy Nelson-Piercy, Consultant Obstetric Physician, Guy’s & St Thomas’
Foundation Trust, London [email protected] Dr Sofia Nyberg, Guy’s and St Thomas’ Medical School, King’s College London [email protected] Dr Catherine Oakley, Chemotherapy Consultant Nurse, Guy’s and St Thomas’ NHS
Foundation Trust, London [email protected] Allan Pacey, Professor of Andrology, University of Sheffield, Sheffield [email protected] Lukasz Polanski, Subspecialty Trainee in Reproductive Medicine and Surgery,
Assisted Conception Unit, Guy’s Hospital, London [email protected]
xiContributors
Professor Daniel Rea, Professor of Medical Oncology, University of Birmingham [email protected] Dr Jonathan Riley, Specialty Registrar in Obstetrics & Gynaecology, Sharoe Green
Unit, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust [email protected] Pippa Sangster, Consultant Urological Surgeon and Andrologist, Clinical Lead for
Male Infertility, University College London Hospital NHS Foundation Trust [email protected] Dr Daniel Saunders, Consultant Clinical Oncologist, The Christie NHS Foundation
Trust, Manchester [email protected] Leighton Seal, The Tavistock and Portman NHS Foundation Trust, London and St
George’s University Hospitals NHS Foundation Trust, London [email protected] Dr Jenny Seligmann, Senior Lecturer and Consultant Medical Oncologist, Leeds
Cancer Centre, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds
[email protected] Majed Shabbir, Consultant Urological Surgeon, Guy’s & St. Thomas’ Hospital,
London [email protected] Francoise Shenfield, Clinical Lecturer in Infertility, Reproductive Medicine Unit,
University College London Hospitals, London [email protected] Katie Snape, Consultant Cancer Geneticist, South West Thames Regional Genetics
Service, St George’s University Hospitals NHS Foundation Trust, London. [email protected] Chara Stavraka, NIHR Academic Clinical Fellow & Specialist Registrar in Medical
Oncology, Guy’s & St Thomas NHS Trust, London [email protected] Dr Mari Thomas, Consultant Haematologist UCLH, NIHR Cardiometabolic
Programme, UCLH/UCL Cardiovascular BRC, London [email protected] Tomlinson, Consultant Genetic Counsellor, Clinical Genetics Service, Guy’s
and St Thomas’ NHS Foundation Trust, London [email protected] Dr Vishakha Tripathi, Consultant Genetic Counsellor, Clinical Genetics, Guy’s & St
Thomas’ NHS Foundation Trust, London [email protected] Miss Lisa Webber, Consultant Gynaecologist and Subspecialist in Reproductive
Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London [email protected]
xii Contributors
Dr Christopher Williams, Clinical Research Fellow and Medical Oncology Registrar, Leeds Cancer Centre, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds
[email protected] Nick Wood, Consultant Gynaecological Oncologist, Royal Preston Hospital,
Lancashire Teaching Hospitals NHS Foundation Trust [email protected]
EditorsDr Caroline Archer, Consultant Medical Oncologist, Portsmouth Oncology Centre,
Portsmouth Hospitals University NHS Trust, Portsmouth [email protected] Ruth E Board, Consultant in Medical Oncology, Rosemere Cancer Centre, Royal
Preston Hospital, Preston [email protected] Dr Melanie C Davies, Consultant Gynaecologist, Reproductive Medicine Unit,
University College London Hospitals, London [email protected] Eleni Karapanagiotou, Consultant Medical Oncologist, Guy’s Cancer Centre, Guy’s
and St Thomas’ NHS Foundation Trust, London [email protected] Julia Kopeika, Consultant Gynaecologist and Subspecialist in Reproductive
Medicine and Surgery, Assisted Conception Unit, Guy’s and St Thomas’ NHS Foundation Trust, London
[email protected] Dr Janine Mansi, Consultant Medical Oncologist, Guy’s and St Thomas’ NHS
Foundation Trust and Biomedical Research Centre, King’s College London [email protected]
Preface
The progress made in cancer diagnosis and treatment has radically improved patient outcomes. More than 50% of people diagnosed with cancer can expect to achieve long-term survival in countries with well-developed healthcare systems. That steady and continuing improvement brings with it the requirement that we focus on the quality of life of cancer survivors. Cancer professionals and patients need to plan carefully together to manage any long-term consequences of cancer and its treatment that they may encounter. Such “Survivorship Care Plans” are widely recommended but not yet comprehensively taken up in all healthcare systems.
Increasing cancer survival rates and the trend towards a later parental age for childbirth mean that there is an increasing chance of a person being diagnosed with cancer before their family is complete. There are increasing numbers of patients for whom fertility following their cancer and its treatment has to be considered carefully; this is a central issue for these patients and professionals. The Association of Cancer Physicians (ACP) has worked with specialists in fertility on Problem Solving in Cancer and Fertility, bringing together the extensive and ever-increasing body of information about the way that cancer and its treatment can affect fertility, the way that fertility can be protected in many patients, and the important aspects of communication and a patient-centred approach which must underpin the provision of cancer care in this most important and sensitive area. The book will discuss exciting technological developments in the preservation and promotion of fertility in cancer patients, which has become a fast-moving field of research and innovation.
Patient concerns about their future fertility are well documented. For example, studies show that over 50% of women diagnosed with breast cancer and ovarian cancer express substantial concerns about impacts on fertility; young men diagnosed with cancer place the retention of fertility as a high priority. However, good quality discussions about fertility do not always occur between cancer patients and healthcare providers. Under some circumstances the cancer care team may prioritise the treatment on curing a cancer; some cancer professionals may lack knowledge of modern fertility preservation. There will be concerns about any risks of delay in treatment, or about increasing emotional distress if fertility is discussed in detail. However, these fertility discussions are central to high-quality survivorship for cancer patients in future. The best cancer care is delivered through a multidisciplinary team; all team members need to be aware of fertility issues for their patients, and some team members should take specific responsibilities to constantly review and audit team practice in this challenging area. The wider multidisciplinary team should involve specialists in fertility, and there need to be clear protocols to involve fertility specialists appropriately when this is needed.
This text on cancer and fertility includes a wide spectrum of issues which are illustrated as chapters and case histories. The perspective chapters cover fertility issues in women and men, including fertility preservation at the time of diagnosis; management, including drugs used during pregnancy; and survivorship issues such as conceiving after treatment, premature ovarian insufficiency, and surrogacy. There are also chapters on issues related to counselling, genetics and ethics. The case histories follow the same pathway as the chapters, but using sometimes complex histories to illustrate the principles and dilemmas.
xiv Preface
The case histories are complementary to the chapters, and there are themes linking clinical scenarios as follows:
Female fertility and fertility preservation:Chapters 1, 2 and Case histories 1, 2, 4, 5, 6, 21, 22
Male fertility and fertility preservation:Chapters 3, 7 and Case histories 3, 7, 23
Cancer in pregnancy:Chapters 4, 5 and Case histories 4, 8, 9, 10,11,
Pregnancy after cancer in women and men:Chapters 6, 9 and Case histories 4, 9, 12, 13, 14, 15, 18, 20, 21, 22, 23
Genetic issues:Chapter 11 and Case histories 5, 19, 22
Premature ovarian insufficiency:Chapters 8, 10 and Case histories 14, 15, 16, 17
Counselling and ethical issues:Chapters 9, 12, 13 and throughout many of the case histories
LGBTQ:Case histories 22, 23
The decision by the Association of Cancer Physicians to focus a workshop and Problem Solving publication on the fertility of cancer patients is a reflection of the progress and success in cancer treatment which we all welcome. However, it also illustrates very well the challenges which we have to face to ensure the best quality of cancer survivorship and the long-term wellbeing of can-cer patients.
Peter Selby, President, Association of Cancer PhysiciansEleni Karapanagiotou, Julia Kopeika, Ruth Board, Caroline Archer,
Melanie Davies, Janine Mansi, EditorsDavid Cunningham, Chair, Association of Cancer Physicians
Acknowledgements
The editors and authors are grateful to all the patients who have inspired us to prepare this book and work together to improve their care.
The editors and authors are very grateful to Cancer Research UK (CRUK) for providing the funding to support this book. The editors, authors and publisher are most grateful to the Association of Cancer Physicians Executive for their support and advice during the development of this book.
We are very grateful to Duncan Enright at EBN Health for his expert work, support, goodwill and interest in our purpose in preparing the book, and Nicole Goldman, who coordinated and oversaw the book’s preparation and organization.
Dr Karapanagiotou, Dr Kopeika and Dr Mansi would like to acknowledge the support of Guy’s and St Thomas’ NHS Foundation Trust. Dr Board would like to acknowledge the support of the University of Manchester and Lancashire Teaching Hospitals NHS Trust. Dr Archer would like to acknowledge the support of Portsmouth Hospitals University NHS Trust. Dr Davies would like to acknowledge the support of University College Hospital NHS Foundation Trust.
Eleni Karapanagiotou, Julia Kopeika, Ruth Board, Caroline Archer, Melanie Davies, Janine Mansi, Editors
Association of Cancer PhysiciansThe ‘Problem Solving’ series of cancer-related books is developed and prepared by the Association of Cancer Physicians (ACP), often in partnership with one or more other specialist medical organizations. In this particular book, our co-editors are representatives from the Royal College of Obstetricians and Gynaecologists, and have a specialist interest in fertility.
As the representative body for medical oncologists in the UK, the ACP has a broad set of aims, including education for our own members and for non-members, including interested clinicians, healthcare professionals and the public. The Problem Solving Series is a planned sequence of publications that derive from a programme of annual scientific workshops initiated in 2014 with ‘Problem Solving in Acute Oncology’ followed by ‘Problem Solving in Older Cancer Patients’, ‘Problem Solving through Precision Oncology’, ‘Problem Solving in Patient-Centred and Integrated Cancer Care’, ‘Problem Solving in Immunotherapy’ and ‘Problem Solving in Acute Oncology 2nd Edition’. ‘Problem Solving in Cancer and Fertility’ is the latest in the series.
The publication involves considerable work from members and other contributors and this work is done without remuneration, as an educational service. We have been delighted with the standard of the publications which have been well received. The BMA prize for Best Oncology Book of the Year was awarded to ‘Problem Solving in Older Cancer Patients’ in 2016, ‘Problem
xvi Acknowledgements
Solving in Precision Oncology’ in 2017 and ‘Problem Solving in Patient-Centred and Integrated Cancer Care’ in 2018.
The ACP wishes to thank all the contributors to this book and our previous publications, and those which are yet to come.
David Cunningham, Chairman, Association of Cancer PhysiciansPeter Selby, President, Association of Cancer Physicians
01P E R S P E C T I V E
01 The Effects of Cancer and its Treatment on Female Fertility
Richard A. Anderson
IntroductionThe treatment of cancer in young women is increasingly turning from focusing purely on survival to recognition of the long-term effects of treatment on subsequent quality of life. In this regard, fertility is a very high priority for patients. That cytotoxic therapies have adverse effects on fertility has been recognized since the very earliest days of the administration of mustard gas derivatives, and specifically in relation to the ovary, with demonstration of the effects of chemotherapeutic agents on growing follicles, resulting in amenorrhea, and in the longer term resulting in loss of fertility and premature menopause. Pregnancy after cancer is also associated with increased risk, notably of prematurity and low birth weight.1 The recognition of the importance of late effects on fertility have been paralleled by a substantial growth in the development and provision of fertility preservation services in reproductive medicine centres and the development of the necessary close links with oncology and other services, although this remains an area where much work needs to be done in improving awareness and access to services in the UK. Fertility preserva-tion is a complex area, requiring a balance between accurate identification of those at risk and the provision of a sufficiently encompassing service, with issues including equality of access, informed decision making regarding the experimental nature of some procedures and provision of funding. From the patient’s perspective, this is all undertaken at very short notice at a time of enormous stress following a recent diagnosis when many other tests and investigations also need to be undertaken. Subsequent fertility is also part of a broader survivorship agenda, recognizing that most cancer survivors have significant health issues which may impact directly or indirectly on their fertility, for example the recognition that survivors of brain and CNS cancers have reduced chance of marriage or co-habitation. There may additionally be concerns about starting or completing a family following such a serious diagnosis, as well as concerns, now recognized to be unsubstantiated, that a pregnancy following, for example breast cancer may increase the risk of recurrence.
Recent developmentsThe effects of chemotherapeutic agents on the ovary will almost invariably involve loss of the growing population of follicles, related to their rapid cell proliferation and sensitivity to cytotoxic agents. This is likely to result in a rapid decline in oestrogen levels, and often amenorrhea. However it is the risk to the non-growing primordial follicle pool that is most important in determining the long-term effects, and potential recovery of the ovary,2 as they constitute the ‘ovarian reserve’. Primordial follicles are formed in fetal life and thereafter a small proportion start to grow every day; subsequently the growing follicles develop fluid-filled cavities (antra) and increasingly produce oestrogen, culminating in ovulation. The number of primordial follicles is therefore progressively depleted over time, with near-exhaustion resulting in the menopause.
S E C T I O N O N E 01
2Problem Solving in Cancer and Fertility Perspective
Premature loss of primordial follicles, as occurs with some chemotherapies, will therefore bring forward the time of the menopause, ultimately during or shortly after treatment. Remaining primordial follicles will start to grow, thus ‘repopulating’ the growing follicle populations of the ovary, with restoration of menses and fertility. This may however be short-lived. Additionally, while the follicle pool is the most important target within the ovary, effects on the vasculature and ovarian stroma are also very relevant and may significantly comprise later follicle growth: these may be affected by chemotherapy as well as radiotherapy. These effects of treatment are depicted in Figure 1.1.
As the primordial follicle pool can only be determined histologically, many studies rely on surrogate biochemical or clinical outcomes. These include anti-müllerian hormone (AMH), which is produced by the smaller antral follicles (Figure 1.1), ultrasound measures of the antral follicle count and most commonly the presence or absence of menses, commonly recorded as chemotherapy related amenorrhea. AMH has become the most useful biomarker of the ovarian reserve in this and other clinical situations, particularly as it does not vary to an important degree across the menstrual cycle. It does however vary in other important clinical situations, most notably being reduced by perhaps as much as 30% in women taking the combined contraceptive pill, and may also be reduced in women with cancer at the time of diagnosis. The more important clinical outcomes are much more difficult to determine and include fertility and age at meno-pause, with other patient-critical outcomes such as time to pregnancy and attaining desired family size, rarely if ever described. The endocrine-related functions of the ovary, for example in sup-porting bone mass and quality of life through recording of issues such as hot flushes and joint pains, are also sometimes investigated and are important aspects of the non-reproductive aspects of ovarian function.
Figure 1.1 Representation of the effects of gonadotoxic treatment on the ovary. The number of primordial and early growing follicles in a healthy ovary is reduced by some chemotherapy regimens, with additional effects on the ovarian vasculature and stroma. If a sufficient population of primordial and thus early growing follicles remains, development of pre-ovulatory follicles will continue allowing the potential for post-treatment fertility. Otherwise, complete depletion results in premature ovarian insufficiency (POI), infertility and oestrogen deficien-cy. Ongoing post-treatment ovarian function may develop into POI, depending on the remaining ovarian reserve.2
Cancer
Bloodvessels
PrimordialFollicles AMH
Oestrogendeficiency
Infertility
Potentialfertility/subfertility
Treatment
GrowingFollicles
Post treatmentamenorrhoea
Recovery, of variable duration
Premature ovarianinsufficiency
AMH
AMH
3Chapter 01: The Effects of Cancer and its Treatment on Female Fertility
In addition to the ovary, the uterus is also a key target of damage through radiotherapy to the pelvis, particular before puberty. Radiotherapy damage to the uterus may result in early or late miscarriage, premature delivery, stillbirth and post-partum haemorrhage.3 The central control pathways of the hypothalamus and pituitary may also be damaged by surgery or cranial radio-therapy, with sometimes subtle but progressive effects on ovulatory control reported.
Due to the progressive decline in the number of follicles within the ovary with age, and the variability from one woman to the next, treatment effects are superimposed on a very wide-ranging background level of ovarian function. The effect of age is well-described, with data showing an increased prevalence of infertility with increasing age at diagnosis even in women with ongoing ovarian function, as well as changes in the prevalence of post-treatment amenorrhea. There are limited data on risk of early menopause, but for example in the case of Hodgkin’s lymphoma, the varying risk with different therapies has been clearly described with minimal risk of early meno-pause following ABVD therapy, but with substantial and increasing risk with alkylating based ther-apy, pelvic radiotherapy and particularly the combination.4 Data relating to fertility after cancer therapy are more scarce, and better provided in the paediatric than adult setting. The United States Childhood Cancer Survivors Study has provided considerable data for many years now, and recent data on women treated with chemotherapy only show the importance of specific therapies but against an overall positive finding of a hazard ratio for live birth of 0.87 (95% CI 0.81–0.92).5 That analysis does however highlight the effect of later age at conception, with a widening of the difference between cancer survivors and their siblings in women who had not conceived before the age of 30. To broaden these data and provide an unbiased risk, we undertook an analysis of population based databases in Scotland recording all diagnoses of cancer up to the age of 40 against subsequent pregnancies, with outcomes compared to the general population standardized for age at diagnosis, interval since and deprivation.6 Overall, this showed that women were 38% less likely to achieve a pregnancy after a cancer diagnosis than women in the general popula-tion and this was across all diagnostic groups (Figure 1.2). Cervical and breast cancer made the
Figure 1.2 Standardized incidence rate (SIR, with 95% CI) for pregnancy after cancer by diagnosis. Data are for female patients (n = 23,201) diagnosed below the age of 40 years between 1981 and 2012 in Scotland, with subsequent pregnancies or death up until the end of 2014, compared to population controls. Standardized for age, deprivation and year of diagnosis. Data from Ref. (6).
0
Cervix
Breast
Brain,
CNS
Leuka
emia
Ovary
Hodgk
inNHL
Colorec
tal
Thyroi
dSkin
0.1
0.2
0.3
0.4
0.5
SIR
± 9
5% C
l
0.6
0.7
0.8
0.9
1
4Problem Solving in Cancer and Fertility Perspective
greatest impact with standardized incidence ratios of 0.34 and 0.39, respectively, but in both cases there have been substantial improvements in the likelihood of achieving a pregnancy across the period of analysis from 1981 to 2012, particularly for cervical cancer (Figure 1.3). This may be an effect of the introduction of cervical screening and thus earlier, less aggressive surgical treatment for cervical cancer, and changes in chemotherapy regimens for breast cancer. For other diagnoses, notably leukaemia and brain/CNS cancers, there has not been any apparent improvement in the chance of pregnancy after diagnosis over these years. Perhaps indicating greater health-awareness after cancer, this analysis also showed that the likelihood of a pregnancy resulting in termination was, in fact, significantly reduced following a cancer diagnosis, particularly in those diagnosed in childhood and adolescence. There were additional improvements in the mode of delivery, with a normalization of the rate of elective caesarean section.1
There has been much interest in the value of the measurement of AMH as an index of cancer treatment induced damage to the ovary, first demonstrated in survivors of childhood cancer despite their continuing to have regular menstrual cycles.7 This finding has been replicated in many other studies and it has also been shown that pre-treatment AMH will predict long-term ovarian function, particularly in the context of breast cancer treatment.8 In that study, all women with pre-treatment AMH <1.9 ng/ml (13.5 pmol/l) showed long-term amenorrhoea, and a value of 0.71 ng/ml (5.0 pmol/l) had peak likelihood ratio of 7 for predicting ongoing menses, with sensitivity 54% and specificity 92%. AMH very clearly distinguishes between high and low risk gonadotoxicity treatments, for example comparing ABVD treatment with BEACOPP: there is complete recovery of AMH levels in women treated with ABVD but only very low post-treatment levels following BEACOPP.9 Intriguingly, however, even following ABVD there was evidence of an impact of age on the rate and extent of recovery, with compromised recovery in women over the age of 35.
Figure 1.3 Adjusted hazard ratio (HR, with 95% CI) for first pregnancy after cancer diagnosis by period of di-agnosis for women with breast, Hodgkin’s lymphoma, cervical, leukaemia and brain/CNS cancers. Reprinted with permission from Ref. (6).
Breast0.0
0.2
0.4
0.6
Adj
uste
d H
R fi
rst p
regn
ancy
0.8
1.0
1.2
Hodgkinlymphoma
Cervix Leukaemia Brain/CNS
1981 - 19881989 - 19961997 - 20042005 - 2012
5Chapter 01: The Effects of Cancer and its Treatment on Female Fertility
While other articles in this series will discuss approaches to fertility preservation, it is now clear from several large randomized control trials that GnRH agonist treatment during chemo-therapy for breast cancer does reduce the prevalence of premature ovarian insufficiency thereaf-ter.10 Meta-analysis indicates an odds ratio of 0.37, with a very similar result from an individual patient data analysis approach, with an odds ratio of 0.38. However, it is important to recognize that these studies only followed-up women for relatively short periods of time, generally no longer than 2 years, and therefore the true benefits of this apparent protective effect on either fertil-ity or the non-reproductive endocrine aspects of ovarian function have not been clearly deter-mined. Notably, the OPTION trial was the only large randomized controlled trial to include AMH measurement to assess ovarian reserve post-treatment, and this showed no difference in AMH levels following recovery between those who did or did not have GnRH agonist treatments during chemotherapy.11 A wide range of other pharmacological approaches to protect the ovary are also being investigated, but these remain in the pre-clinical stage.
ConclusionFertility preservation is now a part of mainstream medicine, which recognizes the im-portance of fertility after cancer treatment to many women. There is an ongoing need for improved accuracy of patient-specific assessment of risk to their fertility and ovarian function, focusing on their proposed treatment, but also in the context of intrinsic issues, notably their age and ovarian reserve. It is to be hoped that in the future, this will allow more tailored and effective use of fertility preservation techniques, with long-term out-come studies also addressing the non-reproductive health benefits of improved ovarian function.
References1 van der Kooi ALF, Kelsey TW, van den Heuvel-Eibrink MM, et al. Perinatal complications
in female survivors of cancer: a systematic review and meta-analysis. Eur J Cancer 2019; 111: 126–37.
2 Jayasinghe YL, Wallace WHB, Anderson RA. Ovarian function, fertility and reproductive lifespan in cancer patients. Expert Rev Endocrinol Metab 2018; 13(3): 125–36.
3 Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2010; 376(9741): 624–30.
4 Swerdlow AJ, Cooke R, Bates A, et al. Risk of premature menopause after treatment for Hodgkin’s lymphoma. J Natl Cancer Inst 2014; 106(9): dju207.
5 Chow EJ, Stratton KL, Leisenring WM, et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016; 17(5): 567–76.
6 Anderson RA, Brewster DH, Wood R, et al. The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod 2018; 33(7): 1281–90.
7 Bath LE, Wallace WH, Shaw MP, Fitzpatrick C, Anderson RA. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 2003; 18(11): 2368–74.
6Problem Solving in Cancer and Fertility Perspective
8 Anderson RA, Cameron DA. Pretreatment serum anti-mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 2011; 96(5): 1336–43.
9 Anderson RA, Remedios R, Kirkwood AA, et al. Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin’s lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial. Lancet Oncol 2018; 19(10): 1328–37.
10 Lambertini M, Moore HCF, Leonard RCF, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data. J Clin Oncol 2018; 36(19): 1981–90.
11 Leonard R, Adamson D, Bertelli G, et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial. Ann Oncol 2017; 28(8): 1811–6.
IndexNote: page numbers in italics refer to figures and tables.
5-fluorouracil, effect on testicular function 155
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) 92, 137
fertility risk 93ovarian toxicity 4–5
acute lymphoblastic leukaemia (ALL) 126–30, 132–5
adolescent boys, sperm cryopreservation 102afatinib
use during pregnancy 121see also tyrosine kinase inhibitors
age, effect on female fertility 3anastrozole 141
alternative treatments 143–4see also aromatase inhibitors
androgen receptor positivity, breast cancer 172–3anthracyclines
cardiotoxicity 124, 134subsequent pregnancy 124, 134use during pregnancy 25, 26
anticoagulationcase study 137–40during pregnancy 27, 139
anti-emetics, use during pregnancy 26, 27anti-müllerian hormone (AMH) 38
as marker of ovarian damage 2, 4–5in pregnancy and post-partum period 83
apixaban 137aromatase inhibitors 146
anastrozole 141alternative treatments 143–4
effect on bone health 147SOFT and TEXT studies 144, 147
artificial ovaries 46, 170Asherman’s syndrome (AS) 164assisted reproduction 31
in azoospermia, case studies 152–5pre-implantation genetic diagnosis 57–8in premature ovarian failure 40–1use of banked sperm 36see also egg donation; in-vitro fertilization; sperm
donationATLAS trial 125atrophic vaginitis 142
aTTom trial 125autonomy 65–6azoospermia 100
assisted reproduction, case study 152–5fertility options 80, 153post-treatment 101
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) 92
fertility risk 93ovarian toxicity 4
BEAM (carmustine, etoposide, cytarabine, melphalan) 137
beneficence 66BEP (bleomycin, etoposide, cisplatin) 177
effects on male fertility 79, 178bereavement support 62bio-identical HRT 39birth defects, incidence 24bisphosphonates 53, 146, 149
adverse effects 149use during pregnancy 27
bone healthcase study 146–50investigations 148osteoporosis/osteopenia management 148–9risk factors for osteoporosis 147–8
Bone Marrow Transplant Survivor Study (BMTSS) 127, 133
bone marrow transplantationeffect on female fertility 127effect on male fertility 127–8long-term health effects 128pregnancy 126–30, 129pre-pregnancy review 128–9
BRAF mutation 88brain/CNS cancer
female fertility preservation 9pregnancy rates after therapy 3, 4
BRCA1 mutation 55, 56ovarian cancer risk 159
BRCA2 mutationbreast cancer in a transgender man 172–5inheritance 159–60ovarian cancer risk 159prophylactic surgery 157–60
182 Problem Solving in Cancer and Fertility
breast cancer 30androgen receptor positivity 172–3case studies
bone health 146–50BRCA2 mutation 157–60fertility preservation 69–71premature ovarian insufficiency 141–4in a transgender man 172–5unexpected pregnancy 111–14
ER positivePOI management 52–3safety of HRT 143safety of ovarian stimulation 70–1safety of vaginal oestrogens 52, 143
fertility preservation 9, 69–71hereditary syndromes 56, 57metastatic, CLEOPATRA trial 112ovarian suppression 158in pregnancy 111–14
diagnosis in pregnancy 20incidence in pregnancy 19treatment 26, 112–13
registries 28breast cancer survivors
assisted reproduction 31breast feeding 31contraception 31–2pregnancy
case study 123–5rates 30safety issues 30–1success rates 3, 4timing of 31
breast feeding 23, 27breast cancer survivors 31, 124
busulphan, effect on female fertility 127
calcium intake 40, 53cancer in pregnancy
breast cancer 111–14delivery
early 23timing of 22
diagnosis 20–1incidence 19–20management 21–2, 27surgery 21systemic anti-cancer treatment 25–7, 26, 28
potential risks 24–5cancer survivors
assisted reproduction 31
contraception 31–2male fertility
assisted reproduction 36natural paternity 35–6spermatogenesis 35
pregnancyneonatal outcomes 31rates 30safety issues 30–1timing of 31
see also breast cancer survivorscapecitabine, effect on testicular function 155carboplatin, effect on male fertility 35cardiotoxicity 124, 128, 134cardiovascular disease risk 39
after bone marrow transplantation 128after oophorectomy 158
case studiesbreast cancer in a transgender man 172–5female fertility preservation
cervical cancer 73–6early breast cancer 69–71ovarian tissue cryopreservation 92–7, 167–70post-partum 82–5
Lynch syndrome 87–90male fertility preservation
inability to produce sperm sample 96testicular cancer 78–81
pregnancyafter bone marrow transplant 126–30after breast cancer treatment 123–5after micro-TESE 152–5after paternal pembrolizumab therapy 105–9after radical trachelectomy 162–5cancer diagnosis 119–22in Hodgkin lymphoma 115–18in metastatic breast cancer 111–14
premature ovarian insufficiency 132–5bone health 146–50HRT and VTE 137–40vaginal symptoms and hot flushes 141–4
salpingo-oophorectomy in BRCA positive breast cancer 157–60
testicular cancer in a gay man 177–80cervical cancer
fertility counselling 75–6fertility preservation 9
case study 73–6incidence in pregnancy 19pregnancy management 75pregnancy rates after therapy 3, 4
183Index
treatment options 74cervical cerclage 75, 126, 165
indications for 129cervical screening, transgender men 175cervical stenosis 162, 163–4checkpoint inhibitors (CPIs)
adverse effects 106fertility implications 107–8pregnancy after paternal use 105–9pregnancy avoidance recommendations 107pregnancy outcomes 106–7use during pregnancy 117
chemotherapyadvice on sexual intercourse 179effects on male fertility 79effects on testicular function 154–5impact on intrauterine growth restriction 22pregnancy avoidance 179see also specific agents and regimens
chlorambucil, effect on testicular function 155chorioamnionitis 163chronic myeloid leukaemia 117
systemic therapy during pregnancy 26–7CLEOPATRA trial 112clomiphene 164colorectal cancer
female fertility preservation 9hereditary syndromes 57pregnancy rates after therapy 3see also Lynch syndrome
combined hormonal contraception (CHC) 39conjugated equine oestrogens 50contraception 31–2
after cervical cancer 75–6combined hormonal 39during SACT 116
controlled ovarian stimulation (COS) 7–8, 167, 169in myelodysplastic syndromes 84–5in post-partum period 83–4safety in ER positive breast cancer 70–1VTE risk 138
counsellingafter trachelectomy 75fertility 60–1
after cervical cancer 75–6gamete donation 62–3welfare of child assessment 61–2
genetic 55, 58in BRCA2 mutation 159–60
in unexpected pregnancy 112, 117Cowden syndrome 57
cranial irradiation, long-term effects 128crizotinib
use during pregnancy 26see also tyrosine kinase inhibitors
CT scans 120cyclophosphamide
effect on female fertility 127effect on testicular function 155use during pregnancy 26
cytotoxic therapyeffects on the ovary 1–2, 4–5use during pregnancy 25–6, 121see also chemotherapy
deep venous thrombosis see venous thromboembolism
dehydroepiandrosterone (DHEA), vaginal 52–3denosumab 149DEXA (dual energy X-ray absorptiometry) 148DHAP (dexamethasone, high-dose cytarabine,
cisplatin) 93directly-acting oral anticoagulants
(DOACs) 139docetaxel 112doxorubicin
effect on testicular function 155subsequent pregnancy 124see also anthracyclines
egg donation 40, 43, 134case study 132–5donor recipient cycles 44donor screening and exclusion criteria 43donor treatment 44ethical issues 67legal aspects 46, 62–3obstetric risks 135pre-treatment preparation 43recipient treatment 44–5source of eggs 45success rates 45
egg retrieval, synchronization with micro-TESE 153–4
egg/embryo cryopreservation 94–5avoidance after recent chemotherapy 93–4case study 69controlled ovarian stimulation 7–8ethical issues 65–7, 66–7freezing methods 8oocytes vs. embryos 8–9, 71time required 70
184 Problem Solving in Cancer and Fertility
electroejaculation (EEJ) 101, 102endocrine cancer, hereditary syndromes 57endometrial cancer
Lynch syndrome 88, 89–90risk from tamoxifen 159survivors, assisted reproduction 31
epirubicinsubsequent pregnancy 124use during pregnancy 112–13see also anthracyclines
erlotinibuse during pregnancy 26, 121see also tyrosine kinase inhibitors
escitalopram 142ethical issues
duration of cryopreservation 66–7gamete donation 62–3general principles 65–6pre-implantation genetic diagnosis 58prenatal diagnosis 58termination of pregnancy 117–18third party assisted reproduction 67welfare of child assessment 61–2
ethinyl oestradiol 50–1etoposide, effect on testicular function 155exemestane
SOFT and TEXT studies 144, 147see also aromatase inhibitors
factor V Leiden 138familial adenomatous polyposis 57familial retinoblastoma 57female fertility 1
age-related effects 3cytotoxic effects on the ovaries 1–2effect of childhood bone marrow
transplantation 127pregnancy rates after cancer therapy 3–4radiotherapy damage to the uterus 3
female fertility preservation 5, 46, 159case studies
breast cancer 69–71cervical cancer 73–6Lynch syndrome 87–90ovarian tissue cryopreservation 92–7post-partum 82–5
diminishing off-target effects 10egg/embryo cryopreservation
controlled ovarian stimulation 7–8ethical issues 65–7
oocytes vs. embryos 8–9, 71preservation methods 8risks 8, 9, 70–1time required 70
funding 10GnRH agonists 10in myelodysplastic syndromes 84–5options 7ovarian tissue cryopreservation 9–10, 70, 95
advantages and limitations 169after first-line chemotherapy 96case studies 92–7, 167–70endocrine function restoration 168procedure 168recent advances 170risks 169subsequent pregnancy 168–9
female infertility management 40–1egg donation 43–6
case study 132–5future concepts 46, 47–8surrogacy 46–8
fertility see female fertility; male fertilityfertility counselling 60–1
after cervical cancer 75–6gamete donation 62–3welfare of child assessment 61–2
Fertility Network UK 63, 64fertility preservation
ethical issuesduration of cryopreservation 66–7general principles 65–6posthumous use 67
hereditary cancer syndromes 56–7see also female fertility preservation; male fertility
preservationfetal metastases 27fluoropyrimidines 89follicle-stimulating hormone (FSH)
controlled ovarian stimulation 7, 8in egg donation 44
FSH Window 7funding 66, 67, 178
gadolinium 83gamete donation
donor contact 63implications of 62–3see also egg donation; sperm donation
gamete preservation methods 8
185Index
gefitinibuse during pregnancy 26, 121see also tyrosine kinase inhibitors
genetic counselling 55in BRCA2 mutation 159–60pre-implantation genetic diagnosis 58
genetic testing 55GnRH agonists 142
in COS 84in egg donation 44female fertility preservation 5, 10
GnRH antagonistsin COS 84in egg donation 44
goserelin 141, 142alternative treatments 143–4
graft-versus-host disease (GvHD) 128granulocyte stimulating factors, use during
pregnancy 26, 27growth factors, use during pregnancy 26, 27
HABITS trial 143haematological cancers
incidence in pregnancy 19see also Hodgkin’s lymphoma; leukaemias;
lymphomahaematometra 162, 164heparin, use during pregnancy 139HER2 targeted therapy 112
effects on pregnancy 113use during pregnancy 26unexpected pregnancy 111–14
hereditary cancer syndromes (HCS) 55, 57fertility preservation 56–7pregnancy 59pre-implantation genetic diagnosis 57–8prenatal diagnosis 58reproductive options 58
hereditary non-polyposis colorectal cancer (HNPCC) 57, 88
see also Lynch syndromehereditary phaeochromocytoma/paraganglioma
syndrome 57Hodgkin’s lymphoma
case studies 92–7, 137unexpected pregnancy 115–18
female fertility preservation, options 94–5male fertility 35pregnancy rates after therapy 3, 4risk of early menopause 3
hormone replacement therapy (HRT) 39–40, 50association with venous thromboembolism
138–9case studies 137–40, 141–4oestrogen 50–1progestogens 51–2risks and benefits 138safety after ER+ve breast cancer 143testosterone, role in women 52
hot flushescase study 141–4management options 142–3non-hormonal treatments 53
Human Fertilisation and Embryology Authority (HFEA)
code of practicegamete donation 43, 46, 62welfare of child assessment 61
donor information provision 63Human Fertilisation and Embryology Authority
Act, 2008 47hypercoagulability 138hypertensive disorders of pregnancy, risk after
oocyte donation 135hypophysitis 106hypothyroidism, effect on pregnancy outcome 129,
130
ICE (ifosfamide, carboplatin, etoposide) 93imaging during pregnancy 20–1, 83, 113, 120
fetal radiation exposure 20imatinib
gonadoprotection 46use during pregnancy 26–7, 117see also tyrosine kinase inhibitors
immunotherapyeffects on testicular function 154–5see also checkpoint inhibitors; monoclonal
antibodiesin-vitro fertilization (IVF)
after radical trachelectomy 162pre-implantation genetic diagnosis 57–8using banked sperm 36using donor eggs 40, 43see also assisted reproduction
in vitro oocyte maturation 95, 170intracytoplasmic sperm injection (ICSI) 100intrauterine adhesions 164intrauterine growth restriction (IUGR) 22intrauterine systems (IUS) 39
186 Problem Solving in Cancer and Fertility
ipilimumabpregnancy avoidance recommendations 107see also checkpoint inhibitors
jaw, medically-related osteonecrosis 149justice 66
legal issuesgamete donation 62–3surrogacy 47, 179
letrozole 146see also aromatase inhibitors
letrozole–FSH protocol 70–1leukaemias, pregnancy rates after therapy 3, 4Li-Fraumeni syndrome 57low-molecular weight heparins (LMWH), use
during pregnancy 139lung cancer
diagnosis during pregnancy 119–22systemic therapy during pregnancy 26
lymphomacase study 167–70female fertility preservation 9see also Hodgkin’s lymphoma
Lynch syndrome 57case study 87–90female fertility issues 89genetic abnormalities 88genetic testing 88pre-implantation genetic testing 89surveillance 89–90
Macmillan Cancer Support 63, 64magnetic resonance imaging (MRI) 20, 83, 113,
120male fertility
cancer survivorsassisted reproduction 36natural paternity 35–6spermatogenesis 35
effect of childhood bone marrow transplantation 127–8
effect of BEP 178male fertility preservation 12–13, 16, 34–5
case studies 78–81, 177–80inability to produce sperm sample 96
options 13service requirements 13in testicular cancer 13–15, 78–81, 177–80use of banked sperm 36
medically-related osteonecrosis of the jaw (MRONJ) 149
melanomaincidence in pregnancy 19metastatic, case study 105
melphalan, effect on female fertility 127menopause, premature see premature ovarian
insufficiencymenstrual suppression, VTE risk 138mercaptopurine, effect on testicular function 155methotrexate, effect on testicular function 155metoclopramide, use during pregnancy 27micro TESE 13, 14, 101
case studies 80, 81, 152–5in post-treatment azoospermia 101retrieval rates 153synchronization with egg retrieval 153–4
microsatellite instability 88Million Women study 39miscarriage
after SACT, case study 115–18incidence 24
mismatch repair (MMR) protein defects 88MLH1 88monoclonal antibodies
breast feeding 27use during pregnancy 25
MSH2 88MSH6 88multiple endocrine neoplasia (MEN) 57myelodysplastic disease, female fertility
preservation 9, 82–5
neurofibromatosis type 1 57nivolumab
pregnancy avoidance recommendations 107see also checkpoint inhibitors
non-Hodgkin’s lymphoma (NHL)case study 167–70female fertility preservation 9
non-maleficence 66norethisterone, menstrual suppression 138
oestradiol preparations 50oestrogen replacement therapy 39–40
doses 51oestrogen formulations 50–1see also hormone replacement therapy
oestrogen-sensitive cancersPOI ma nagement 52–3
safety of HRT 143safety of ovarian stimulation 70–1safety of vaginal oestrogens 52, 143
oncofertility services 13, 14–15, 16
187Index
onco-microTESE 14, 80, 81ondansetron, use during pregnancy 27oocytes
production from stem cells 46see also egg donation; egg/embryo
cryopreservationoophorectomy
case study 157–60long-term health effects 158
OPTION trial 5osteoblastic osteosarcoma 99–104osteoporosis/osteopenia 39, 53
case study 146–50investigations 148management 148–9risk after oophorectomy 158risk factors for 147–8
ovarian cancerfertility preservation 9hereditary syndromes 56incidence in pregnancy 19Lynch syndrome 88, 89–90pregnancy rates after therapy 3risk in BRCA carriers 159
ovarian hyperstimulation syndrome (OHSS) 8ovarian reserve 1–2
assessment 69, 70, 132, 133post-partum period 83
biomarkers of 2ovarian stimulation see controlled ovarian
stimulationovarian suppression 158ovarian tissue cryopreservation 9–10, 70, 95
advantages and limitations 169after first-line chemotherapy 96case studies 92–7, 167–70endocrine function restoration 168procedure 168recent advances 170risks 169subsequent pregnancy 168–9
ovaries, effects of cytotoxic therapy 1–2ovulation suppression, post-partum period 83oxybutynin 143
paraganglioma 57paroxetine 142partner status 177–8PD-1, PD-L1 expression, relationship to pregnancy
loss 107pembrolizumab
pregnancy after paternal use 105–9
see also checkpoint inhibitorspercutaneous epididymal sperm aspiration
(PESA) 13, 101pertuzumab 112
effects on pregnancy 113Peutz–Jeghers syndrome 57phaeochromocytoma 57phytoestrogens 52placental metastases 27platinum-based therapy
effect on testicular function 155effects on female fertility 89effects on male fertility 79use during pregnancy 25, 26, 121
PMS2 88polycarbophil preparations 142polycystic ovary syndrome (PCOS) 162POSITIVE study 124posthumous use of cryopreserved material 67post-partum fertility preservation 82–5post-partum VTE risk 84pregnancy
anticoagulation 27, 139cancer survivors 30, 75, 123–30, 162–5
neonatal outcomes 31safety issues 30–1timing 31
cardiotoxicity-related risks 134case studies
after bone marrow transplant 126–30after breast cancer treatment 123–5after paternal pembrolizumab therapy 105–9after radical trachelectomy 162–5cancer diagnosis 119–22in metastatic breast cancer 111–14
chemotherapy during 112–13delivery
early 23timing of 22, 121
diagnosis of cancer 20–1, 83, 119–22discovery after cancer diagnosis 20effects of anti-HER2 therapy 113hereditary cancer syndromes 59hypothyroidism 129, 130imaging 20–1, 83, 120incidence of cancer 19–20intrauterine growth restriction, impact of
treatment 22management 21–2, 27in premature ovarian failure 41radiation exposure, fetal doses 20surgery 21
188 Problem Solving in Cancer and Fertility
pregnancy (continued)systemic anti-cancer treatment 25–7, 26, 28
potential risks 24–5thromboprophylaxis 139thrombosis risk 22, 27after trachelectomy 75unexpected
counselling 112, 117management of 105, 112–14, 115–18
pregnancy status policies 116pre-implantation genetic diagnosis (PGD) 57–8
Lynch syndrome 89premature ovarian insufficiency (POI) 1–2, 2, 38
after oestrogen-sensitive cancers 52–3case studies 132–5
bone health 146–50HRT and VTE 137–40vaginal symptoms and hot flushes 141–4
definition 38diagnosis 38fertility options 134health consequences 39health surveillance 41hormone replacement therapy 39–40, 50
oestrogen 50–1progestogens 51–2testosterone 52
infertility management 40–1egg donation 43–6future concepts 46
investigations 142lifestyle advice 40risk assessment 70risk in Hodgkin’s lymphoma 3spontaneous pregnancy 40, 133survivorship issues 38VTE risk 52
premature rupture of membranes (PROM) 163prenatal diagnosis (PND) 58primordial follicle pool 1–2primordial follicles, in vitro growth 170progestogen replacement therapy 51
doses 51–2IUS 39
prophylactic surgeryBRCA positive breast cancer 157–60, 174Lynch syndrome 90
prostate cancer 56pulmonary embolism see venous thromboembolism
radical trachelectomy 74cervical stenosis 163–4fertility and obstetric outcomes 74–5, 163subsequent pregnancy 75
case study 162–5radiography see imaging during pregnancyradiotherapy
childhoodeffect on female fertility 127effect on male fertility 127–8obstetric risks 134
dose required to cause POI 133–4effect on the uterus 3fetal radiation exposure 22testicular 79
R-AVD (rituximab, doxorubicin, vinblastine, dacarbazine), accidental pregnancy 115–18
refractory anaemia with excess blasts (RAEB) 82–5retinoblastoma 57
salpingo-oophorectomy, risk-reducing 157–60, 174same-sex couples
case study 177–80fertility rights 178
selective oestrogen receptor modulators (SERMS)endometrial effects 159see also tamoxifen
selective serotonin reuptake inhibitors (SSRIs) 142seminoma 178serotonin-noradrenaline reuptake inhibitors
(SNRIs) 142–3sexual intercourse, advice during
chemotherapy 179sexual orientation 177–8sildenafil 99, 100skin cancer
pregnancy rates after therapy 3see also melanoma
slow-freezing gamete preservation 8SOFT study 144, 147sperm cryopreservation 13, 100
in adolescent boys 102after micro-TESE 153–4assisted reproduction 36case studies 78–81
inability to produce sperm sample 96counselling 178–9ethical issues 65–7indications for 34–5
189Index
prior investigations 179referral for 34retrieval techniques 13, 14
electroejaculation 101sildenafil 100surgical options 101, 153
in testicular cancer, optimal timing 79–80sperm donation 153
ethical issues 67implications of 62–3
spermatogenesiseffect of immune checkpoint inhibitors 107effect of testicular cancer treatment 79effects of chemotherapy and
immunotherapy 154–5recovery post-treatment 35
spermatogonial stem cell (SSC) preservation 13stem cell transplantation (SCT), case study 132–5Stockholm trial 143surgery, prophylactic
BRCA positive breast cancer 157–60, 174Lynch syndrome 90
surgery during pregnancy 21impact on intrauterine growth 22
surrogacy 46clinical aspects 46–7ethical issues 67financial aspects 47, 178–9legal aspects 47, 179screening 47
systemic anti-cancer treatment (SACT)breast feeding 27effects on testicular function 154–5during pregnancy 25–7, 28, 120–1
risks 24–5, 26pregnancy avoidance 116pregnancy status policies 116see also checkpoint inhibitors; chemotherapy;
cytotoxic therapy
T-scores 148, 149tamoxifen
and breast feeding 124duration of treatment 125endometrial cancer risk 159gonadoprotection 46interruption of treatment for pregnancy 123–4and pregnancy 26SOFT and TEXT studies 144, 147
vulval and vaginal actions 144taxanes, use during pregnancy 25, 26, 112–13termination of pregnancy
ethical issues 117–18grounds for 117
testicular cancerazoospermia, fertility options 80case studies
fertility preservation 78–81in a gay man 177–80
effect on fertility 79fertility preservation 13–15, 78–81staging 178subfertility rates 78–9
testicular cryopreservation 102testicular dysgenesis syndrome 79testicular function, effects of chemotherapy and
immunotherapy 154–5testicular sperm aspiration (TESA) 13, 101testicular sperm extraction (TESE) 13,
101, 153in adolescent boys 102case study 99in post-treatment azoospermia 101see also micro TESE; onco-microTESE
testosterone therapymanagement in breast cancer patients 173–4role in women 52
TEXT study 144, 147thrombosis see venous thromboembolismthyroid cancer, pregnancy rates after therapy 3tibolone 51topoisomerase inhibitors, effect on testicular
function 155trachelectomy 74
cervical stenosis 163–4fertility and obstetric outcomes 74–5, 163subsequent pregnancy 75
case study 162–5transgender men
breast cancerandrogen receptor positivity 172–3case study 172–5follow-up 173specific challenges 175surgical options 173testosterone management 173
cervical screening 175fertility options 174
190 Problem Solving in Cancer and Fertility
trastuzumab 112effects on pregnancy 113use during pregnancy 26unexpected pregnancy 111–14
tyrosine kinase inhibitorsbreast feeding 27use during pregnancy 25, 26–7, 117, 121
ultrasonography 20, 120United States Childhood Cancer Survivors Study 3uterine bioengineering 48uterine transplantation 48uterus
haematometra 162, 164intrauterine adhesions 164radiotherapy damage 3, 127, 134
vaginal dehydroepiandrosterone 52–3vaginal moisturisers 142vaginal oestrogens 142
use after oestrogen-sensitive cancers 52, 143vaginal symptoms of POI
case study 141–4management options 142and tamoxifen 144
vasomotor symptomscase study 141–4management options 142–3non-hormonal treatments 53
venlafaxine 142–3venous thromboembolism (VTE)
association with HRT 138–9case study 137–40in hormone replacement therapy 39, 52post-partum 84during pregnancy 26, 27prevention in pregnancy 139risk factors for 138
Virchow’s triad 138vitamin D supplementation 40, 53vitrification 8, 65–6Von Hippel–Lindau syndrome 57
welfare of child (WOC) assessment 61–2withdrawal bleeds 51Women’s Health Initiative 39
X-raysfetal radiation exposure 20during pregnancy 83, 120